Temporal trends in mortality and causes of death in patients with incident atrial fibrillation: a nationwide register study from 2010 to 2018

Objectives
Atrial fibrillation (AF) is associated with increased mortality. Previous studies have reported conflicting results in temporal trends of mortality after AF diagnosis. We aim to address this disparity by investigating the 1-year mortality and causes of death in Finnish patients diagnosed with AF between 2010 and 2017.

Design
The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) study is a nationwide retrospective register-based cohort study.

Setting
The FinACAF study has gathered information on all Finnish AF patients between 2004 and 2018, with information from all national healthcare registers and data from all levels of care (primary, secondary and tertiary care).

Participants
We included patients with an incident AF diagnosis (International Classification of Diseases, 10th Revision code I48) between 2010 and 2017. To ensure a cohort of only incident AF, we excluded patients who used any oral anticoagulant during the year before cohort entry as well as patients with a recorded use of warfarin between 2004 and 2006. Patients under 20 years of age were excluded, and patients with permanent migration abroad before 1 January 2019 were excluded, N=157 658.

Primary outcome measures
1-year all-cause, cardiovascular (CV) and cause-specific mortality following AF diagnosis.

Results
The study cohort consisted of 157 658 incident AF cases (50.1% male, mean age 72.9 years). Both all-cause and CV mortality declined from cohort entry years 2010–2017 (from 12.9% to 10.6%, mortality rate ratio (MRR) 0.77; 95% CI 0.73 to 0.82 in cohort entry year 2017 with 2010 as reference; and from 7.4% to 5.2%, MRR 0.68; 95% CI 0.63 to 0.74, respectively). Overall mortality and CV mortality were lower in women than in men throughout the study period (MRR 0.66; 95% CI 0.63 to 0.69 and MRR 0.53; 95% CI 0.50 to 0.56, respectively). Deaths attributable to ischaemic heart disease decreased during the study period (from 30.7% to 21.6%, MRR 0.51; 95% CI 0.49 to 0.62 in 2017 vs 2010), whereas dementia and Alzheimer’s disease increased as a cause of death over time (6.2% to 9.9%, MRR 1.19; 95% CI 0.96 to 1.48 in 2017 vs 2010). The CHA2DS2-VASc score associated strongly with 1-year survival (p

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Alzheimers disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis

Objective
Mutations in presenilin genes are the major cause of Alzheimer’s disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis.

Design
Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis.

Results
Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation.

Conclusion
Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD.

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